1. Historical figures in schizophrenia research
Emil Kraepelin
1883: “Dementia Praecox”
separated schizophrenia from bipolar disorder (manic-depressive psychosis) based on the clinical course of the syndromes
Eugene Bleuler
1911: “Schizophrenia” – 1909: Genetic
splitting of the mind  between thought and emotion
Associations
Affect
Ambivalence
Autism

5. Epidemiology Prevalence ~1%; male = female
Right now over 2 million adult Americans have schizophrenia
Seen in all cultures at similar frequency
Onset usually late adolescence to young adulthood, earlier in males than females
(reactive: leaving home, loss of parent, 1st sex experience)
Increased chance of being born in the winter or early spring

7. Prevalence of Selected DSM-IV Axis I Disorders
M F Total
Major Depression
Panic Disorder
Social Phobia
Schizophrenia

8. Prevalence relative to medical disorders

9. Schizophrenics have:
Increased mortality rate from accidents and natural causes:
life span is shortened by about a decade
some under-diagnosis of medical illness is present
~10-15% suicide; ~50% attempt
early in illness and young age
high premorbid function
depression
the latter two often contributing to demoralization
Illness seems concentrated in urban settings, i.e., it is somewhat correlated with population density in larger cities
Illness seems concentrated in lower socioeconomic classes (1/3 of homeless)

10. Diagnosis of Schizophrenia
A. Characteristic symptoms: > 2 of 5 (active phase symptoms – Criterion A)
delusions
hallucinations
disorganized speech (incoherence-”word salad”)
grossly disorganized or catatonic behavior
negative symptoms, i.e., affective flattening, alogia, or avolition
* bizarre delusions or running commentary voices or voices conversing with each other

11. Diagnosis of Schizophrenia
B. Social/occupational dysfunction (50% unemployed)
Duration: at least 6 mo. (include at least 1 month of symptoms from Criterion A)
D&E. Mood Disorder, Substance/general medical condition exclusion
F. No Pervasive Developmental Disorder: (ex:Autism) (only if prominent delusions or hallucinations are also present for at least a month)

12. Subtypes Catatonic Disorganized (hebephrenic) Paranoid
Catatonic behavior dominates (catalepsy-muscle rigidity/agitation)
Less common nowadays
Disorganized (hebephrenic)
Disorganized speech, behavior, and affect (flat or inappropriate)
Paranoid
Delusions and/or auditory hallucinations
Not limited to persecutory themes
Tends to have a later onset and better course

13. Etiology of Schizophrenia Genetic Influences

14. Adoption Studies
Implies genetic factors not environmental

16. Genetics and Family Studies

18. Etiology of Schizophrenia Brain Abnormalities

19. Hippocampus

20. Due to virus (Flu) 2nd trimester: adhesion molecules causing pathological migration

22. Frontal Lobe Issues Functional brain imaging (PET, rCBF)
Failure to increase blood flow to the dorsolateral prefrontal cortex while performing the activation task of the Wisconsin Card Sorting Test
Reduced blood flow to the left globus pallidus (an even earlier finding in the course of illness) suggests a problem in the system connecting the basal ganglia to the frontal lobes
Correlation with severity of disease present

23. Wisconsin Card Sorting Task
Subjects are asked to sort each upcoming card on to one of the four piles (they are not directed but may use shape, color or number). They are told correct/incorrect. Whichever category they choose is correct for a given number of categories then is met with an “incorrect” response. Subjects must “switch sets” to get a correct response. Failure to switch sets is termed “perseveration”.
Schizophrenic subjects perseverate relative to normal controls, Green et al, 1992

25. Frontal Lobe Abnormalities - PET image of twins during WCST

26. Ventricles Enlarged

28. MRI – Discordant

30. (bigger differences in males- ventricle size

31. Post-Mortem Neuroanatomy Disturbed connection between thalamus and PFC
Schematic diagram summarizing disturbances in the connectivity
between the mediodorsal (MD) thalamic nucleus and the dorsal
prefrontal cortex (PFC) in schizophrenia. Postmortem studies have
reported that subjects with schizophrenia have 1) decreased number
of neurons in the mediodorsal thalamic nucleus; 2) diminished
density of parvalbumin-positive varicosities, a putative marker of
thalamic axon terminals, selectively in deep layers 3-4, the
termination zone of MD projections to the PFC; 3) preferential
reduction in spine density on the basilar dendrites of deep layer 3
pyramidal neurons, a principal synaptic target of the excitatory
projections from the MD; 4) reduced expression of the mRNA for
glutamic acid decarboxylase (GAD67), the synthesizing enzyme for
GABA, in a subset of PFC GABA neurons; 5) decreased density of
GABA transporter (GAT-1)-immunoreactive axon cartridges, the
distinctive, vertically-arrayed axon terminals of GABAergic
chandelier neurons, which synapse exclusively on the axon initial
segment of pyramidal neurons; 6) decreased dopamine innervation
of layer 6, the principal location of pyramidal neurons that provide
corticothalamic feedback projections (From Lewis & Lieberman,
Neuron 28: , 2000.).

34. Serendipity Strikes Again!!!!

35. 1960 – discovery that striatums (caudate putamens) depleted of Dopamine

36. Dopamine Hypotheses of Schizophrenia
Schizophrenia due to over activity

37. Dopamine of Antagonist

41. Clorpromazine (Carlsson, 1963)
- expected DA levels to decrease
Metabolite increased
D2 receptor blockers work not
because to much dopamine but
Because to many receptors or too
Sensitive…

42. Dopamine Hypotheses of Schizophrenia (revised)
Positive symptoms of schizophrenia attributed to hyperdopaminergic function (more receptors or increased sensitivity, etc, D2)

46. Evidence in Support

47. Dopamine hypothesis - weaknesses:
Some atypical antipsychotics such as clozapine are not as well correlated with respect to D2 dopamine receptor binding and clinical potency
Does not account for negative symptoms of schizophrenia

48. Evidence against DA hypothesis of Schizophrenia – Glutamate???
Disorganized thought symptoms of schizophrenia attributed to hypofunctional glutamate system
Glutamate antagonists such as PCP and ketamine mimic disorganized thought, may also cause psychosis and negative symptoms?